Human T-lymphotropic virus type III (HTLV-III)/lymphadenopathy-associated virus (LAV) is a newly discovered retrovirus that is cytopathic for helper/inducer T cells in vitro. The virus is the etiologic agent of the acquired immune deficiency syndrome (AIDS) and related diseases. To date, thousands of cases of AIDS have been reported in the United States alone, and the incidence and prevalence of this disease continue to increase. AIDS is almost always fatal within 1 to 2 years after the first clinical manifestations of illness. This disease was initially described and characterized in four high-risk groups (homosexual men, hemophiliacs, Hatians, and intravenous drug abusers); however, individuals belonging to no apparent high-risk groups have also developed the disease. AIDS is generally spread by intimate sexual contact or by the administration of infected blood products, and occasionally by the maternal-fetal route. Many patients who develop AIDS are asymptomatic when they transmit their disease to contacts because a 6-month to 5-year (or more) latency interval may exist between infection and clinical manifestations of illness.
Although there is no effective therapy for AIDS, a number of compounds are currently under study as HTLV-III/LAV inhibitors, both in clinical trials and in model systems. Retroviral DNA polymerase (reverse transcriptase) plays a unique and essential role in the life cycle of HTLV-III/LAV, and this enzyme can be a target for antiviral therapy. Among the potential drugs being studied for use against AIDS which inhibit this enzyme are suramin and its analogs, ribavirin, foscarnet, and HPA-29. Biological response modifiers such as alpha and gamma interferon, interleukin-2, and monoclonal antibodies are also being evaluated. Comparative data for a number of these materials have recently been reviewed by B. J. Oberg in Antimicrob. Chemo. 1986, 17, 549-551. Although a number of anti-viral agents are currently being considered for experimental therapy of AIDS, to data no therapy has been shown to cure HTLV-III/LAV infection, or to completely restore the underlying immunodeficiency. Moreover, the chronicity of the infection, and the propensity of the virus to infect the brain, make it necessary to explore new classes of drugs that have the potential of oral administration and penetration across the blood-brain barrier.
Historically, nucleosides have been among the best antiviral drugs for treating DNA and RNA viral infections. Several known active agents of this class [e.g., 3-azido-3'-deoxythymidine (AZT), ribavirin] have been evaluated against HTLV-III/LAV in vitro, and AZT, a compound with activity in test systems, is currently in Phase I/II clinical trials. Other compounds which have been found to be effective in protecting cells against the cytopathic effects of HTLV-III/LAV in vitro are 2',3'-dideoxy (dd) analogs of physiologically important nucleosides.
These compounds, as their 5'-triphosphates, are known to terminate growing DNA chains because they lack the 3'-hydroxyl group required for further polymerization. This termination process forms the basis for the Sanger DNA sequencing method. While different cell types appear to vary significantly in their aibilities to phosphorylate 2',3'-dideoxynucleosides to the mono-, di-, and triphosphate levels, the corresponding end product triphosphates are known to strongly inhibit reverse transcriptase, as well as beta and gamma DNA polymerase. However, DNA polymerase alpha, the key synthetic enzyme for the DNA replication during cell growth, is much less affected.
While the 2',3'-dideoxy analogs of adenonsine (ddA), guanosine, inosine, thymidine, and cytidine (ddC) are all very effective in protecting T4.sup.+ lymphocytes against the cytopathic effects of HTLV-III/LAV in vitro, 2',3'-dideoxycytidine appears to be the most potent member of the group on the basis of molarity. At the non-cytotoxic concentrations of 0.5 and 5.0 micromoles, ddC provided essentially 100% protection to T4.sup.+ lymphocytes exposed to what would be an otherwise cytopathic dose of HTLV-III/LAV virus. However, some dideoxy nucleosides, e.g., ddA, are not very soluble in water or body fluids, and therefore is difficult to formulate for easy intravenous administration.